The Mitsunobu Reaction

SCHEME 6.31 The nitromethane condensation can provide amine-substituted sugars and sugar precursors. 

SCHEME 6.32 The Mitsunobu reaction can dehver phthahmides to sugars and sugar derivatives. 

The Mitsunobu reaction, discovered by Oyo Mitsunobu (1934-2003) in 1967, is one of the most important among modern synthetic reactions. It allows the replacement of the OH group of primary and secondary alcohols with a variety of nucleophiles, with clean inversion of stereochemistry and under mild conditions. The key reagents are triphenylphosphine and a dialkyl azodicarboxylate the latter is very often diethyl azodicarboxylate (DEAD). In addition, a key requirement is that the nucleophile should be acidic (for reasons you ll see below) carboxylic acids, phenols, thiols, imides, and activated carbon acids are all appropriate nucleophiles. 

How does one come up with a cocktail such as the above—an alcohol, a nucleophile, PPh3, and DEAD Insight, a lucky observation or two, and tinkering all surely played a role. 

The key objective here is to convert the OH group, normally a lousy leaving group, to an excellent one that can be displaced by the added nucleophile. This is where PPh3 and 

DEAD come in they react together to form a betaine intermediate, as shown below  

The betaine then deprotonates the protonated form of the nucleophile  

In the Mitsunobu reaction, a chiral 2° alcohol and a carboxylic acid are converted to an ester with clean inversion at the electrophilic C. The reaction requires PI13P and Et02CN=NC02Et (diethyl azodicarboxylate, DEAD). It is usually carried out by adding DEAD slowly to a mixture of the alcohol, PI13P, and the nucleophile in its protonated form. 

The reaction is clearly not a simple Sn2 displacement of OH from R by PhC02, because HO is a really awful leaving group in Sn2 reactions and will not leave under these mild conditions, and besides, PI13P and DEAD are required for the reaction. But equally clearly, Sn2 displacement must happen at some point, or clean inversion at R could not occur. 

Balancing the equation shows that H2O has been lost. Whenever PI13P is used in a reaction, it is almost always converted to Ph3PO. The other by-product, then, must be Et02CNHNHC02Et. Because a single Sn2 displacement has occurred at the alcohol C, both O atoms in the product must come from benzoic acid, which means that the former alcohol O must end up attached to PI13P. Both the alcohol O and P are nucleophilic, so the role of the DEAD must be to convert one of them from a nucleophile into an electrophile. DEAD itself is a potent electrophile, with two electrophilic N atoms. 

The first part of the mechanism of the Mitsunobu reaction involves addition of nucleophilic Ph3P to the electrophilic N in DEAD. (The alcohol could add to DEAD instead, but P is far more nucleophilic.) The addition is preceded by protonation of DEAD by the carboxylic acid. 

In the second part of the mechanism, the carboxylate displaces N from P in Sn2 fashion, giving an acyloxyphosphonium ion and a nitrogen anion. The latter then deprotonates the alcohol, generating an alkoxide, which displaces P from O to give an alkoxyphosphonium ion and to regenerate the carboxylate. 

Balancing the equation shows that H2O has been lost. Whenever Ph3P is used in a reaction, it is almost always converted to Ph3PO. The other by-product, then. 

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A very mild and efficient synthesis of N-substituted -lactams uses the Mitsunobu reaction (see section 2.6.2) for the ring closure of seryl dipeptides protected at the terminal N as 4,5-diphenyloxazol-2(3f/)-one ( Ox ) derivatives (see section 2,6.3)... 

The Mitsunobu reaction is usually used to introduce an ester with inversion of configuration. The use of this methodology on an anomeric hydroxyl was found to give only the /3-benzoate, whereas other methods gave mixtures of anomers. Improved yields are obtained in the Mitsunobu esterification when p-nitrobenzoic acid is used as the nucleophile/ Bis(dimethylamino) azodicarboxylate as an activating agent was... 

The Mitsunobu reaction is used to convert an alcohol and an acid into an ester by the formation of an activated alcohol (Ph3P, diethyl diazodicar-boxylate), which then undergoes displacement with inversion by the carboxylate. Although this reaction works very well, it suffers from the fact that large quantities of by-products are produced, which generally require removal by chromatography. 

Primary alcohols may be phosphorylated by use of the Mitsunobu reaction (Ph, , DEAD, HBF4, Pyr). Of several salts examined, the potassium salt of the phosphate was the best. 

The Wenker aziridine synthesis entails the treatment of a P-amino alcohol 1 with sulfuric acid to give P-aminoethyl sulfate ester 2 which is subsequently treated with base to afford aziridine 3. Before the discovery of the Mitsunobu reaction, wbicb transforms an amino alcohol into an aziridine in one step under very mild conditions, the Wenker reaction was one of the most convenient methods for aziridine synthesis. However, due to the involvement of strong acid and then strong base, its utility has been limited to substrates without labile functionalities. 

The major application of the Mitsunobu reaction is the conversion of a chiral secondary alcohol 1 into an ester 3 with concomitant inversion of configuration at the secondary carbon center. In a second step the ester can be hydrolyzed to yield the inverted alcohol 4, which is enantiomeric to 1. By using appropriate nucleophiles, alcohols can be converted to other classes of compounds—e.g. azides, amines or ethers. 

In summary the Mitsunobu reaction can be described as a condensation of an alcohol 1 and a nucleophile—NuH—11, where the reagent triphenylphosphine is oxidized to triphenylphosphine oxide and the azodicarboxylate reagent 12 is reduced to a hydrazine derivative 13 ... 

Suitable starting materials for the Mitsunobu reaction are primary and secondary alcohols. Tertiary alcohols are less suitable since these are bad substrates for a SN2-mechanism. 

The Mitsunobu reaction was applied to the synthesis of pyrrolo[l,2-d [, 2,4]triazines from pyrrole derivative 71. Thus reduction of 71 gave alcohol 72, which on treatment with diethylazodicarboxylate and triphenyl phosphine gave 74 via the open chain intermediate 73. Hydrolysis of 74 gave 75 (84AG517) (Scheme 18). 

The Mitsunobu reaction was also applied to the synthesis of [ 1,2,4]triaz-ino[4,5-n]indoles (84AG517). Thus, reaction of the 2-acylindoles 127 with sodium borohydride in methanol or with lithium aluminium hydride in tetrahydrofuran gave the corresponding alcohols 128. Their cyclization with diethyl azodicarboxylate in the presence of triphenyl-phosphine gave the triazinoindoles 129. Acid treatment of the latter afforded 130 (Scheme 30). 

The synthesis of 6-azidomethyl-S,6,7,8-tetrahydropterin 108 has been carried out from 106 via the intermediate 107 using the Mitsunobu reaction with diphenylphosphoryl azide followed by deprotection <95MI09 %CA(124)232123>. 

A unique preparation of 2,3 5,6-di-O-isopropylidene-a-D-mannofuran-osyl fluoride (45) utilizing the Mitsunobu reaction [diethyl azodicarboxy-late (DEAD)-triphenylphosphine in the presence of EtjO BFi ii this case] has been reported (see Table 1). 

The role of the DEAD is to activate the triphenylphosphine toward nucleophilic attack by the alcohol. In the course of the reaction the N=N double bond is reduced. As is discussed later, this method is applicable for activation of alcohols to substitution by other nucleophiles in addition to halide ions. The activation of alcohols to nucleophilic attack by the triphenylphosphine-DEAD combination is called the Mitsunobu reaction.76... 

Entry 10 illustrates the application of the Mitsunobu reaction to synthesis of a steroidal iodide and demonstrates that inversion occurs. Entry 11 shows the use of the isolated Ph3P-Br2 complex. The reaction in Entry 12 involves the preparation of a primary iodide using the Ph3P-I2-imidazole reagent combination. 

Diphenylphosphoryl azide reacts with alcohols in the presence of triphenylphosphine and DEAD.76 Hydrazoic acid, HN3, can also serve as the azide ion source under these conditions.77 These reactions are examples of the Mitsunobu reaction. 

Triphenylphosphine reacts with peroxides to give intermediates that are related to those formed in the Mitsunobu reaction. The following reactions are examples ... 

What properties of the intermediates in the Mitsunobu reaction are suggested by these reactions ... 

The Mitsunobu reaction late in the synthesis was low yielding and generated excessive waste. 

Develop alternatives to the Mitsunobu reaction to improve yield and to reduce... 

A new Ullmann ether protocol to install the pyrrolidinylethanol 10 was developed, obviating the need for the Mitsunobu reaction. 

Since the first examples of lower and upper rim glycocalixarenes were obtained in 1994 by Marra el al.,106 employing the Mitsunobu reaction or copper(II)-catalyzed glycosylation, the development of efficient synthetic methodologies has allowed the emergence of several examples of ()-, N-, or C-glycosyl calix arenes, and these have recently been reviewed (101-106, Fig. 8).107,10X... 

The Mitsunobu reaction offers a powerful stereochemical transformation. This reaction is very efficient for inverting the configuration of chiral secondary alcohols since a clean SN2 process is generally observed ( Mitsunobu inversion ). Considering the fact that Mitsunobu chemistry is typically carried out at or below room temperature, high-temperature Mitsunobu reactions performed under microwave con-... 

For X=OH and R=EWG group or alkyl, the Mitsunobu reaction (10) is evidently the most convenient procedure for the synthesis of the corresponding nitronates (35a) (Scheme 3.34). 

Scheme 21 shows the synthesis of a dihydrofuran derivative 86. Synthesis of this compound was described by Nam et al. [68] utilizing a furanone compound 87 synthesized by Kim et al. [61] via a similar synthetic approach as described in Scheme 17. The lactone was reduced using lithium aluminum hydride to give the diol 88 and intramolecular etherification using the Mitsunobu reaction afforded the dihydrofuran 86 in moderate yield (47%).

The corresponding syn-compound can also be synthesized by simply inverting the stereochemistry of the hydroxyl group of the epoxy alcohol by the Mitsunobu reaction [54], Therefore, this method provides a simple and reliable method for the synthesis of any enantiomers and diastereomers of straight-chain 1,2-polyols. 

The glycosylation based on the Mitsunobu reaction has been most commonly directed to the synthesis of O-aryl glycosides, a structural motif found in a variety of natural products [80-82], Early work by Grynkiewicz [83,84], among others [85-87], established the viability of triphenylphosphine and diethylazodicarboxylate to promote the glycosylation of phenol acceptors at ambient temperature. More recently, Roush and coworkers have discovered that the glycosylation performed well in the... 

Epimerization of carbohydrate stractures to the corresponding epi-hydroxy stereoisomers is an efficient means to generate compounds with inverse coirfiguration that may otherwise be cumbersome to prepare. Several different synthetic methods have been developed, including protocols based on the Mitsunobu reaction,sequential oxidation/reduction... 

Weinges, K. Haremsa, S. Maurer, W., The Mitsunobu Reaction on Methyl Glycosides as Alcohol Component. Carbohydr. Res. 1987, 164, 453-458. 

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